DESCRIPTION (applicant's abstract): Opioids are the most powerful analgesic agents presently available. However, there are significant limitations to their effectiveness. The general goal of the proposed research is to elucidate the circuitry underlying opioid analgesia and to determine the factors that limit the analgesic efficacy of opioids. This proposal is focused on opioid activated circuitry at the level of the brainstem and spinal cord. The rostral ventromedial medulla (RVM) is involved in brainstem control of nociceptive transmission. Opioid receptors and endogenous opioid peptides are found in this region, and microinjection of opioid agonists into RVM suppresses behavioral responses to noxious stimulation. Three classes of putative nociceptive modulating neurons have been identified in the RVM: Off cells, which suppress nociceptive transmission, are activated by morphine. On cells, which facilitate nociceptive processing, are inhibited by morphine. The other RVM neurons, neutral cells, are unaffected by morphine. We will use intracranial microinjection techniques, behavioral tests of nociceptive responsiveness, in vivo and in vitro single unit recording and application of putative neurotransmitter receptor agonists and antagonists to investigate RVM circuitry. We plan to determine how each class of RVM neuron modulates spinal cord dorsal horn nociceptive transmission. Another important goal of these studies is to determine the contribution of the mu, kappa, delta and orphanin opioid receptors to RVM-mediated modulation of nociception. Hopefully, by increasing knowledge of what limits the efficacy of opioid analgesia, new pharmacological strategies can be devised to produce more potent and selective analgesics.